Antibodies to cyclic citrullinated peptides in psoriatic arthritis

OBJECTIVE: To determine the presence and clinical significance of antibodies to cyclic citrullinated peptides (anti-CCP) in psoriatic arthritis (PsA). METHODS: We performed a cross-sectional study on 102 outpatients (56 men) with PsA consecutively recruited from a tertiary referral center. Median disease duration was 36 months (interquartile range 21-81). All patients were investigated for peripheral joint and axial involvement, enthesitis, and dactylitis. Laboratory investigations included anti-CCP, assessed by enzyme-linked immunosorbent assay and IgM rheumatoid factor (RF). Plain radiographs of pelvis, wrists, hands, and feet were performed in all cases. RESULTS: Anti-CCP were detected in 16/102 patients, 8/68 with symmetric polyarthritis, 1/8 with asymmetric polyarthritis, 2/20 with mono-oligoarthritis, 1/2 with mutilating arthritis, and 0/4 with exclusive axial or distal interphalangeal (DIP) involvement. The male:female ratio as well as frequency of dactylitis, enthesitis, and nonexclusive axial or DIP joint involvement were similar in the anti-CCP positive and negative groups. Anti-CCP positive patients were more frequently treated with disease modifying antirheumatic drugs and showed higher number of involved joints, and higher frequency of erosive arthritis and positive RF. Using multiple logistic regression, anti-CCP (but not RF) were significantly associated with erosive arthritis (odds ratio 9.8; 95% confidence interval 1.87-51.8) and > or = 10 involved joints (17.99; 3.6-89.2). CONCLUSION: Anti-CCP can be found in a small but significant proportion of patients with a clinical picture of PsA and are associated with erosive arthritis and multiple joint involvement.     

Antibodies directed to cyclic citrullinated peptides in familial Mediterranean fever

The aim of this study was to find the prevalence of anti-cyclic citrullinated peptide (anti-CCP) in patients with familial Mediterranean fever (FMF) and to examine the relationship between anti-CCP and joint findings. We measured the serum levels of the anti-CCP antibodies in patients with FMF (n = 55) and healthy controls (n = 43). Serum levels of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, ferritin, erythrocyte sedimentation rate (ESR), and white blood cell (WBC) were also measured in all the samples. Fibrinogen, ferritin, erythrocyte sedimentation rate (ESR), and RF levels were normal in the patient and the control groups (P > 0.05). There was a significant difference in anti-CCP between the patient and the control groups (P = 0.008). There was a positive correlation between arthritis and anti-CCP (P = 0.001). In patients without arthritis, there was no significant relationship between abdominal pain or fever and anti-CCP (P > 0.05). Anti-CCP levels increased in FMF patients with arthritis independent from acute phase reactants such as CRP, ESR, and fibrinogen. We conclude that in patients who are under investigation for arthritis, the ones with positive anti-CCP and negative RF, may be examined for FMF. In addition, we also conclude that it is very likely that FMF patients with anti-CCP antibodies will have signs of arthritis. On the other hand, it is possible that long-term follow-up of the FMF patients with anti-CCP antibodies may reveal the eventual development of inflammatory joint disease.     

Antibodies to viral citrullinated peptide in rheumatoid arthritis

OBJECTIVE: To analyze the frequency of anti-viral citrullinated peptide (anti-VCP) antibodies in sera from patients with rheumatoid arthritis (RA) by an Epstein-Barr virus (EBV)-derived peptide in which arginine is replaced with citrulline.METHODS: Anti-VCP antibodies were determined in 627 serum samples, 300 from patients with RA and 327 from controls, including connective tissue diseases, chronic arthritides, and healthy donors. Among patients with RA, a possible correlation with systemic involvement, disease severity, and disease activity was investigated; in 94 RA patients antibodies to cyclic citrullinated protein (anti-CCP) were also measured. RESULTS: Anti-VCP antibodies were found in 45% of RA sera versus less than 5% of controls; anti-VCP levels correlated with anti-CCP levels (p < 0.0001), rheumatoid factor (p = 0.02), and erythrocyte sedimentation rate (p = 0.0058). No correlation was found with extraarticular manifestations of the disease or with disease severity. CONCLUSION: Anti-VCP antibodies are helpful in discriminating RA from other chronic arthritides or connective tissue disorders. The level of positivity is positively correlated with the anti-CCP level, suggesting that VCP can be considered a novel substrate to detect anti-citrullinated peptide/protein antibodies (ACPA). The reactivity of RA-specific antibodies with a viral citrullinated antigen raises questions on the role of EBV in the induction of ACPA.     

Antibodies to citrullinated proteins in arthritis: pathology and promise

PURPOSE OF REVIEW: The purpose of this review is to describe how the current knowledge of antibodies to citrullinated protein antigens in rheumatoid arthritis and related conditions emerged; to discuss the diagnostic and prognostic value associated with antibodies to citrullinated protein antigens as a biomarker; and most importantly for this review, to discuss the potential pathogenetic significance of these antibodies. RECENT FINDINGS: Antibodies to citrullinated protein antigens have evolved from being mainly a diagnostic marker, to being recognized as something that can help us understand fundamental etiologic and pathogenetic features of rheumatoid arthritis. Fundamental in this context is the finding that rheumatoid arthritis can be divided into two distinct subsets by means of presence or absence of antibodies to citrullinated protein antigens. Thus, several genetic as well as environmental risk factors differ between these two variants of rheumatoid arthritis. From analysis of these genetic and environmental risk factors, new testable hypotheses have been produced concerning triggering of antibodies to citrullinated protein antigens, and potential pathogenicity of antibodies to citrullinated protein antigens and accompanying immune reactions. SUMMARY: The implications of the findings are that antibodies to citrullinated protein antigens can be used for early and precise diagnosis of a subset of rheumatoid arthritis with worse prognosis than other polyarthritides, and that a new basis is formed for etiologic and pathogenetic studies of antibodies to citrullinated protein antigens-positive rheumatoid arthritis.     

Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment

To evaluate antibodies against cyclic citrullinated peptides (anti-CCP) together with rheumatoid factor (RF), antinuclear antibodies (ANA) and C-reactive protein (CRP), in patients affected by rheumatoid arthritis (RA), before and after infliximab treatment. Twenty-seven patients (five men and 22 women, mean age of 51.9 years, mean duration of disease 12.6 years) affected by RA, refractory to conventional DMARDs, were treated with infliximab, at the conventional dosage. Before starting infliximab and after 22 weeks, on the occasion of the fifth infusion, anti-CCP antibodies were tested by ELISA method. At the same time IgM RF, ANA and CRP level were measured. Before infliximab therapy, anti-CCP antibodies resulted positive in 23 patients (85.1%); the serum level did not change after infliximab treatment; only one case negative at baseline became slightly positive after treatment. Before and after therapy RF resulted positive in 22 cases (81.4%) and 21 cases (77.7%) respectively; comparing values at baseline with those after 22 weeks of treatment with infliximab, RF levels significantly decreased, as well as CRP values. In contrast to both anti-CCP antibodies, which remained stable, and to RF, which fell after infliximab, ANA were positive 1: 160 in four cases at baseline and in 12 after treatment. The titre of anti-CCP antibodies did not significantly change after anti-TNF blocker administration; instead the positivity of RF significantly decreased. As opposed to antinuclear and anti-dsDNA antibodies, which may appear or increase in titre during infliximab treatment, the typical autoantibodies detectable in RA show a different trend; in fact, anti-CCP antibodies remained stable and RF decreased.     

Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides

OBJECTIVE: The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA-specific anti-Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti-MCV) as compared with antibodies against cyclic citrullinated peptides (anti-CCP) in an inception cohort of patients with early RA. METHODS: Clinical data, radiographs, and measurements of levels of anti-MCV and anti-CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls. RESULTS: Of the 273 patients, 193 (70.7%) were anti-MCV positive and 158 (57.9%) were anti-CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti-MCV positive only, and 5 (1.8%) were anti-CCP positive only. Anti-MCV-positive and anti-MCV-negative patients had similar disease activity at baseline, but presence of anti-MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti-MCV level showed stronger correlation with changes in clinical parameters than did changes in anti-CCP level. The subgroup of patients who were anti-MCV positive and anti-CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti-MCV and anti-CCP. CONCLUSION: These findings show that when patients with early RA are compared with healthy controls, analysis of anti-MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti-CCP. Anti-MCV also appears to perform better than anti-CCP in identifying poor radiographic prognosis in patients with early RA.     

儿童系统性红斑狼疮抗环瓜氨酸肽抗体检测及其临床意义

目的 检测儿童系统性红斑狼疮(JSLE)患者血清抗环瓜氨酸肽(CCP)抗体水平,了解抗CCP抗体在该病中的阳性检出率以及探讨其与关节炎表现相关性.方法 采用第3代抗CCP抗体酶联免疫吸附试验(ELISA)检测47例JSLE、54例幼年特发性关节炎(JIA)患者和40名年龄匹配的健康儿童血清中抗CCP抗体水平,并分析该抗体与JSLE实验室指标及临床特征,尤其是关节表现之间关系.正态分布的计量资料比较采用t检验,非正态资料比较采用Mann-Whitney U检验,率的比较采用χ2或Fisher精确检验.结果 47例JSLE患儿中6例为抗CCP抗体阳性,抗体阳性率明显高于健康对照组(13%与0,P＜0.05),与JIA组(26%)差异无统计学意义(P=0.098).抗CCP抗体阳性JSLE患儿中类风湿因子(RF)阳性率显著高于阴性患者(83%与15%,P＜0.01),在其他实验室指标和包含关节炎发生率等临床特征方面差异均无统计学意义(67%与51%,P＞0.05).47例JSLE患儿中以关节炎起病者25例,无一例出现关节畸形或影像学改变,关节受累与未受累者间抗CCP抗体水平及阳性率比较差异均无统计学意义(16%与9%,P＞0.05);3例在长达3年病程中始终伴有关节疼痛、活动受限患儿抗CCP抗体均呈阴性.结论 抗CCP抗体可在系统性红斑狼疮患儿血清中检出,在同JIA作鉴别诊断时应引起重视,但抗CCP抗体与JSLE关节炎发生、持续并无明显联系.     

Antibodies targeting mutated citrullinated vimentin in patients with psoriatic arthritis

Antibodies against mutated citrullinated vimentin (anti-MCV) are of a comparable diagnostic value in rheumatoid arthritis (RA) as antibodies targeting citrullinated peptides (anti-CCP). Anti-CCP are present in up to 15% of psoriatic arthritis (PsA) patients, while the prevalence of anti-MCV in PsA patients has been poorly investigated. The aim of the present study was to assess the prevalence and relevance of anti-MCV antibodies in PsA patients. The study included 56 PsA patients. Clinical features, disease activity, and functional ability were noted by an experienced rheumatologist. Serum samples of all patients were analyzed for anti-MCV and anti-CCP antibodies using enzyme-linked immunosorbent assay. Data on 92 patients with RA, 44 patients with other inflammatory rheumatic diseases, and 107 healthy controls from a previous study were used to compare the prevalence of anti-MCV antibodies in PsA patients. Anti-MCV antibodies were positive in only two out of 56 (3.6%) PsA patients, which was significantly lower compared to RA patients (63%). The anti-MCV level was moderately positive and borderline in one patient each. Both patients had asymmetric polyarthritis, dactylitis, moderate to high disease activity, and were anti-CCP and rheumatoid factor (RF) negative. There was no significant difference in anti-MCV levels according to clinical subtypes of PsA and no correlation of anti-MCV levels with anti-CCP, RF, disease activity variables, and functional ability indices. According to study results, anti-MCV antibodies can be detected in a very small proportion of PsA patients with polyarthritic disease and are primarily related to the polyarthritic pattern rather than the specific diagnosis of RA.     

Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients

Objective

High titers of specific anti–citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well‐defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA‐specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well‐defined HLA–DR groups.

Methods

Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age‐ and sex‐matched healthy controls were analyzed for the presence of anti‐MCV and anti‐CCP antibodies and for reactivity to citrullinated fibrinogen, α‐enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA–DR shared epitope alleles.

Results

Significantly higher proportions of antibodies against all RA‐associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non–RA‐associated anti–tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA–DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients.

Conclusion

MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti‐CCP+/anti‐MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA‐predisposing genes.

     

Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis

OBJECTIVES: To find out whether autoantibodies to citrullinated telopeptides of type I and II collagens and to cyclic citrullinated peptides (CCPs) predict the development of rheumatoid arthritis (RA). METHODS: A case-control study (matched for sex, age and municipality) was nested within a Finnish cohort of 19072 adults who had neither arthritis nor a history of it at the baseline examination during 1973-7. 124 subjects developed RA by late 1989, and of these, 89 were positive for rheumatoid factor (RF). Preillness serum specimens were analysed for autoantibodies against arginine (A)- or citrulline (C)-containing synthetic telopeptides using a chemiluminescence method and for anti-CCPs Mark2 with an enzyme-linked immunosorbent assay method. RESULTS: The mean levels of autoantibodies to citrulline-containing telopeptides and the C/A ratios of type I and II collagens and to CCP were higher in subjects who later developed RF-positive RA. In the highest tertiles of C/A (I), C/A (II) ratios and anti-CCPs levels, the relative risk of RF-positive RA was significantly increased. In the multifactorial model, only anti-CCPs retained its statistical significance. However, the interaction term of C/A (II) ratio and anti-CCPs proved to be statistically significant (p = 0.02). The subjects ranked into the highest tertiles of both C/A (II) ratio and anti-CCPs had an odds ratio of 20.06 (95% confidence interval, 4.37 to 92.06) of developing RF-positive RA compared with those in the lowest tertiles of these antibodies. None of the autoantibodies predicted RF-negative RA. CONCLUSION: Autoantibodies to citrullinated telopeptides of type I and II collagen and to CCPs exert a synergistic effect on the risk of seropositive RA.     

Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis

BACKGROUND: The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synovium OBJECTIVE: To assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test. METHODS: In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests. RESULTS: The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (kappa = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8). CONCLUSIONS: ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.